The present invention relates to 1,3-bis-(N-lactamyl)propanes and their use as solvents in pharmaceutical and cosmetic compositions.
A priority requirement in the development of an optimal administration form for a drug is that the bioavailability be good. As a rule, the most favorable conditions for this are provided by solutions of the active ingredient used, irrespective of whether a product for injection, a liquid oral drug form or, for example, a soft gelatin capsule preparation is concerned.
However, the solubility of many drugs in water is too low for them to be administered parenterally in the form of an aqueous solution, for example. Recourse is therefore frequently had to other solvents, for example organic, aqueous/organic or oily solvents.
It is important in the selection of suitable solvents to ensure that certain requirements are met. The solvent which is used must not be toxic, nor must it increase the toxicity of the active ingredient dissolved therein. It is, of course, necessary for the solvent to be compatible with the active ingredient, and it must not lead to inactivation or decomposition. Furthermore, the solvent must not induce irritation, sensitization or an allergic reaction either, and it should also be suitable for heat sterilization. For parenteral purposes, the viscosity should be low enough for injection with a relatively thin needle to be possible.
In addition, miscibility with other solvents, such as physiological saline or an infusion solution for preparing a product for injection or the oily vehicle in a soft gelatin capsule preparation, is important.
Besides water, well-known solvents are, for example, low molecular weight polyethylene glycols, 1,2-propylene glycol, ethanol, glycerol, benzyl alcohol, dimethylacetamide or neutral oils such as paraffin, castor oil or mixtures of triglycerides of saturated vegetable fatty acids.
However, the properties of the abovementioned solvents are not always satisfactory. Thus, the miscibility with other solvents may be limited, or the volume of solvents required to dissolve the active ingredient is so large that physiological tolerability is no longer ensured. For example, the widely used propylene glycol is immiscible with fixed oils. Benzyl alcohol has the disadvantage that its solubility in water is only 4%. Although glycerol is miscible with water, it is not soluble in fixed oils. In addition, the maximum glycerol concentration which can be used is limited to about 5% for tolerability reasons. Dimethyl-acetamide has very good dissolving properties but the tolerability is relatively poor so that use in humans does not appear acceptable.
The use of pyrrolidone derivatives such as 2-pyrrolidone, N-methylpyrrolidone and hydroxyethylpyrrolidone as solvents or cosolvents is known.
For example, EP-A 271 374 describes aqueous antibiotics compositions for veterinary use in which a tetracycline is dissolved in N-(hydroxyethyl)-2-pyrrolidone.
EP-A 626 171 discloses injection solutions for intravenous or intramuscular administration of oxytetracycline or doxycycline, the solvent phase being formed by N-methylpyrrolidone and/or 2-pyrrolidone.
A mixture of 2-pyrrolidone and N-methyl-2-pyrrolidone comprises the pharmaceutical vehicle of a composition for the cosmetic and therapeutic treatment of human beings and animals which is described in DE 26 15 140.
Although the formulations based on pyrrolidone derivatives described above have good solubility properties, they do not meet the strict requirements to be met by drugs, because the physiological tolerability is unsatisfactory. Furthermore, the absorption times are relatively long, and the serum levels achieved therewith are in need of improvement.
Nor do the bis- or poly-(N-pyrrolidonyl)alkanes described in the prior art sufficiently comply with the strict requirements to be met by pharmaceutical solvents. Thus, the asymmetric polypyrrolidonyl compounds of U.S. Pat. No. 3,989,815 are not at all intended for use as solvents; on the contrary they are used only as dispersants. The bis(N-pyrrolidonyl)alkanes described in U.S. Pat. No. 5,326,880 as vehicles for pharmaceutical compositions administered topically dissolve many active ingredients to only a limited extent. They are therefore unsuitable for pharmaceutical preparations where good solubility of the active ingredient matters.
It is an object of the present invention to provide solvents for pharmaceutical preparations which, besides an excellent dissolving capacity for the active ingredient used, also provide excellent miscibility with other solvents and good physiological tolerability.
We have found that this object is achieved by certain, asymmetric 1,3-bis-(N-lactamyl)propanes which are excellent solvents for a large number of active ingredients of low solubility in water and, furthermore, can be used universally because they are miscible in any ratio with other conventional pharmaceutical solvents. The compounds according to the invention are chemically inert and show high physiological tolerability.
The present invention relates to the use of at least one 1,3-bis(N-lactamyl)propane of the formula I 
where R1, R2, R3, R4, R5 and R6 are, independently of one another, hydrogen, alkyl, cycloalkyl, aryl or aralkyl, and at least one of these radicals is not hydrogen, (NLac) and (NLacxe2x80x2) are identical or different and are N-lactamyl radicals, as solvents in pharmaceutical or cosmetic compositions.
The term xe2x80x9calkylxe2x80x9d comprises straight-chain or branched alkyl groups, preferably C1-C10-alkyl, in particular C1-C6-alkyl and, particularly preferably, C1-C3-alkyl, such as methyl, ethyl, n- and i-propyl, n-, i- or t-butyl, n-pentyl, neopentyl or n-hexyl, etc.
xe2x80x9cCycloalkylxe2x80x9d comprises cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and polycyclic radicals such as norbornyl, camphyl, pinanyl or decahydronaphthyl, it being possible for both the mono- and the polycyclic radicals to be substituted by one or more C1-C4-alkyl groups.
The term xe2x80x9carylxe2x80x9d comprises aromatic radicals, preferably naphthyl and, in particular, phenyl.
xe2x80x9cAralkylxe2x80x9d means aryl groups which are connected via a C1-C4-alkylene unit to the basic framework. xe2x80x9cAralkylxe2x80x9d is preferably benzyl.
xe2x80x9cAlkylenexe2x80x9d means linear or branched divalent alkyl radicals, preferably C1-C6-alkylene and, in particular, C1-C4-alkylene, such as methylene, 1,1- and 1,2-ethylene, 1,1-, 1,2-, 1,3- and 2,2-propylene, 2-methyl-1,1-propylene etc.
The term xe2x80x9cN-lactamylxe2x80x9d represents N-substituted mono- or polycyclic lactams which may be substituted by C1-C4-alkyl groups, C1-C4-alkoxy groups or halogen, and/or be fused to aromatic systems, and/or contain further hetero atoms, preferably nitrogen or oxygen, in the lactam ring. Particularly preferred N-lactamyl radicals are derived from pyrrolidone, piperidone, xcex4- or xcex5-caproactam, 4-oxazolidinone or tetrahydro-1,4-oxazin-3-one and, in particular, from pyrrolidone.
In 1,3-bis-(N-lactamyl)-propanes according to the invention which are preferably used as solvents in pharmaceutical compositions, at least one of the radicals R1, R2, R3, R4, R5 and R6 is alkyl, while the remainder of these radicals are hydrogen.
Particularly suitable compounds of the formula I are those where only one of R1, R2, R3, R41 R5 and R6 is not hydrogen, with R1 being preferred in this case and being, in particular, alkyl.
In a particular embodiment, 1,3-bis-(N-lactamyl)butanes are used, i.e. compounds of the formula I where R1 is methyl.
The lactamyl groups (NLac) and (NLacxe2x80x2) in formula I may be identical or different, but they are preferably identical.
A particular class of compounds for use as solvents in pharmaceutical preparations are those compounds of the type described above which have no center of symmetry. Compounds of this type result when the substituted propylene unit is asymmetric per se and/or the lactamyl radicals NLac and NLacxe2x80x2 are different. Preferred compounds are those where the propylene unit is asymmetric and the two lactamyl radicals have the same meaning.
The following compounds are very particularly preferred:
1,3-Bis(1-pyrrolidonyl)butane
1,3-Bis(1-piperidonyl)butane
1,3-Bis(1-caprolactamyl)butane
1,3-Bis(tetrahydro-1,4-oxazin-3-on-1-yl)butane
1,3-Bis(oxazolidin-4-on-3-yl)butane
1-(1-Caprolactamyl)-3-(1-piperidonyl)butane
3-(1-Caprolactamyl)-1-(1-piperidonyl)butane
1-(1-Caprolactamyl)-3-(1-pyrrolidonyl)butane
3-(1-Caprolactamyl)-1-(1-pyrrolidonyl)butane
1-(1-Caprolactamyl)-3-(oxazolidin-4-on-3-yl)butane
3-(1-Caprolactamyl)-1-(oxazolidin-4-on-3-yl)butane
1-(1-Caprolactamyl)-3-(tetrahydro-1,4-oxazin-3-on-4-yl)butane
3-(1-Caprolactamyl)-1-(tetrahydro-1,4-oxazin-3-on-4-yl)butane
1-(Oxazolidin-4-on-3-yl)-3-(1-piperidonyl)butane
3-(Oxazolidin-4-on-3-yl)-1-(1-piperidonyl)butane
1-(Oxazolidin-4-on-3-yl)-3-(1-pyrrolidonyl)butane
3-(Oxazolidin-4-on-3-yl)-1-(1-pyrrolidonyl)butane
1-(Oxazolidin-4-on-3-yl)-3-(tetrahydro-1,4-oxazin-3-on-4-yl)-butane
3-(Oxazolidin-4-on-3-yl)-1-(tetrahydro-1,4-oxazin-3-on-4-yl)-butane
1-(1-Piperidonyl)-3-(1-pyrrolidonyl)butane
3-(1-Piperidonyl)-1-(1-pyrrolidonyl)butane
1-(1-Piperidonyl)-3-(tetrahydro-1,4-oxazin-3-on-4-yl)butane
3-(1-Piperidonyl)-1-(tetrahydro-1,4-oxazin-3-on-4-yl)butane
1-(1-Pyrrolidonyl)-3-(tetrahydro-1,4-oxazin-3-on-4-yl)butane
3-(1-Pyrrolidonyl)-1-(tetrahydro-1,4-oxazin-3-on-4-yl)butane.
Some of the compounds which are suitable according to the invention and are described above have one or more asymmetric carbon atoms and may therefore exist in different stereochemical forms. This invention relates both to the individual isomers (enantiomers or diastereomers) and to mixtures thereof.
The preparation of compounds of the formula I is known in principle. Thus, Breitenbach et al. (Naturwissenschaften 42, 1955, 155; 440) describe the dimerization of N-vinylpyrrolidone under acidic reaction conditions and subsequent hydrogenation of the resulting 1,3-bis-(N-pyrrolidonyl)-1-butene to 1,3-bis -(N-pyrrolidonyl)butane. Based on this procedure, it is possible as shown in scheme I to prepare, by acid-catalyzed reaction of the vinyllactams of the formula Ia or IIb, where Ra, Rb, Rc and Rd are, independently of one another, hydrogen, alkyl, cycloalkyl, aryl or aralkyl, and (NLac) and (NLacxe2x80x2) are the abovementioned lactamyl radicals, the propenes of the formula IIIa-d. The compounds III a-d are subsequently converted by hydrogenation into the corresponding compounds of the formula I a-d. The compounds I a-d correspond to those compounds of the formula I in which two radicals on adjacent carbon atoms, for example R1 and R5, are hydrogen. When mixtures of two vinyllactams of the formula II are used, it is possible to obtain both the mixed reaction products and the two products of a reaction of the vinyllactams II with themselves. The compounds can be separated both at the stage of the propenes IIIa-d and at the stage of the final products Ia-d, but this is not always necessary for preparing the solvents according to the invention. Preferably prepared in this way are the compounds I obtained by reaction of the vinyllactams IIa and IIb with themselves (Ia and Id respectively). 
The vinyllactams of the formula Ia or IIb which are employed are known or can be prepared by general processes based on the preparation of the known vinyllactams II. There are no restrictions on the configuration of the olefinic double bonds in the compound of the formula II.
The vinyllactams II can be converted into the bis-(N-lactamyl)-propenes III by conventional methods of acid-catalyzed dimerization of olefins using a protic acid, a Lewis acid catalyst or Ziegler catalysts (see, for example, J. March, Advanced Organic Chemistry 3rd ed., page 709 and literature cited therein). The reaction can take place either without diluent or else in an inert solvent, eg. a halogenated hydrocarbon such as CH2Cl2, aromatic compounds such as toluene, ethers such as diethyl ether, dioxane or tetrahydrofuran, or another solvent which is suitable for electrophilic reactions. Preferred catalysts are strong protic acids, preferably those with corresponding anions of low nucleophilicity, such as sulfuric acid, sulfonic acids, eg. p-toluenesulfonic acid, methanesulfonic acid or trifluor-methanesulfonic acid, perchloric acid or hydrogen chloride. The acid is preferably employed in substoichiometric amount based on the vinyllactams, in particular in catalytic amount and, particularly preferably in amounts of up to 5 mol % . The reaction is preferably carried out at temperatures in the range from xe2x88x9220xc2x0 to +60xc2x0 C. and, in particular, in the range from 10xc2x0 to 40xc2x0 C.
The subsequent hydrogenation step can take place by the conventional processes for hydrogenating olefinic double bonds (see J. March, Advanced organic Chemistry, 3rd ed., pages 691-708 and literature cited therein), preferably by catalytic hydrogenation with hydrogen on transition metal catalysts. Because of their enamine characteristics, the double bonds in the propene moiety of III display high reactivity which permits this double bond to be hydrogenated selectively in the presence of other, less reactive double bonds.
Another route to 1,3-bis-(N-lactamyl)propanes consists of reacting 1,3-diamines of the formula IV, where R1, R2, R3, R4, R5 and R6 have the meanings stated above for I, with suitable lactones (see scheme II; OLac is the lactone corresponding to the relevant N-lactamyl radical (N-Lac)). 
U.S. Pat. No. 5,326,880 describes this procedure for the example of the preparation of 1,3-bis-(N-pyrrolidonyl)pentane. The procedure indicated therein can be applied to the preparation of the compounds of the formula I according to the invention.
Another possibility for preparing compounds of the formula I starts from 1,3-functionalized compounds of the formula V where X and Y, which can be identical or different, are suitable leaving groups, eg. halide, tosylate, brosylate or trifluoromethane-sulfonate, and R1, R2, R3, R4, R5 and R6 have the abovementioned meanings. Compounds of this type are reacted with suitable N-lactamyl anions to give the 1,3-bis-(N-lactamyl)propanes of the formula I (scheme III). The particular lactamyl anions (NLac)xe2x88x92 are obtainable as a rule by treating the lactams (N-NLac) with suitable bases such as alkali metal or alkaline earth metal hydroxides, alcoholates, alkali metal hydrides or amides. The reaction of the compounds V with the anions of the lactams can be carried out by conventional methods for N-alkylation of amides (cf. J. March, Advanced organic Chemistry, 3rd ed., pages 377 et seq. and literature cited therein). It is moreover possible for the 1,3-difunctionalized compounds V to be reacted either with the lactams in the presence of a base or else with the anions of the lactams which have been previously generated. If X and Y differ in reactivity, it is possible, especially in the latter case, to obtain compounds of the formula I with different lactamyl radicals. 
Suitable 1,3-difunctionalized compounds are starting materials frequently employed in organic synthesis and can be obtained, for example, starting from aldoles by modification of the functional groups by known processes or starting from cyclopropanes by halo-genating cleavage of the cyclopropane unit.
The present invention also relates to 1,3-bis(N-lactamyl)propanes of the formula Ia 
where (NLac) and (NLacxe2x80x2) identical or different and are N-lactamyl radicals.
The N-lactamyl radicals in the abovementioned compounds are preferably derived from, in particular, unsubstituted pyrrolidones, piperidones, xcex4- or xcex5-caprolactam, tetrahydro-1,4-oxazin-3-ones or 4-oxazolidinones. Pyrrolidone, piperidone or xcex5-caprolactam particularly preferred. (NLac) and NLacxe2x80x2) preferably have the same meaning.
The N-lactamyl radicals preferably represent pyrrolidone. However, interesting compounds are also produced if at least one of the, and in particular both, N-lactamyl radicals, which may be identical or different, have a ring with at least 6 members.
The use according to the invention of the 1,3-bis-(N-lactamyl)-propanes of the formula I as solvents extends to all pharmaceutical preparations which are known to the skilled worker and in which the active ingredient(s) is (or are) used in dissolved form. Formulations of these types can be administered orally, ophthalmologically, rectally, parenterally, (for example by the intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intrathoracic, intraarterial, intracardiac, intraspinal, intrasynovial-routes etc.), intraarticularly, topically, nasally or buccally. Suitable presentations comprise capsules, for example soft gelatin capsules, embrocations, lotions, applications, creams, ointments, gels, drops, self-propellant formulations and spray formulations.
The compounds according to the invention are particularly employed for preparing pharmaceutical compositions for systemic and, in particular, parenteral, and topical, use. The compounds of the formula I are particularly suitable as solvents for injectable products, for example preparations for injection and infusion, and in the contents of capsules, for example soft gelatin capsules. Parenteral preparations which contain the compounds according to the invention in combination with polyvinylpyrrolidones have proven particularly advantageous. The polyvinylpyrrolidone content is preferably in the range from 1 to 70%, preferably 5 to 60%, of the total weight of the combination. It is possible on use of a combination of this type to produce parenteral preparations, in particular injectable products, with a long-lasting action.
In topical products, the compounds according to the invention are able to increase the rate of absorption of active ingredients.
The present invention also relates to pharmaceutical compositions which contain at least one 1,3-bis(N-lactamyl)propane of the formula I. Besides these compounds according to the invention, the pharmaceutical composition contains at least one active ingredient with or without other conventional vehicles and/or ancillary substances.
The amount of active ingredient per dose unit and the concentration may vary within wide limits. The only condition is that they suffice to achieve the desired effect. It is also possible to employ combinations of active ingredients. Active ingredients for the purpose of the invention include vitamins and minerals, an d crop treatment agents and insecticides. Active ingredients for the purpose of the invention also include therapeutic peptides. Hydrophilic active ingredients are particularly suitable.
The solvents according to the invention can be used to dissolve the following active ingredients, for example:
Acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, alprazolam, alfacalcidol, allantoin, allopurinol, ambroxol, ambkacin, amiloride, aminoacetic acid, amiodarone, amitriptyline, amlodipine, amoxicillin, ampicillin, ascorbic acid, aspartame astemizole, atenolol, beclomethasone, benserazide, benzalkonium hydrochloride, benzocaine, benzoic acid, betamethasone, bezafibrate, biotin, biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine, budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine, carbidopa, carboplatin, cefachlor, cefalexin, cefadroxil, cefazolin, cefixime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, selegiline, choramphenicol, chlorhexidine, chlorpheniramine, chlortalidone, choline, cyclosporin, cilastatin, cimetidine, ciprofloxacin, cisapride, cisplatin, clarithromycin, clavulan acid, clomipramine, clonazepam, clonidine, clotrimazole, codeine, cholestyramine, cromoglycic acid, cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpanthenol, dextromethorphan, dextropropoxiphen, diazepam, diclofenac, digoxin, dihydrocodeine, dihydroergotamine, dihydroergotoxin, diltiazem, diphenhydramine, dipyridamole, dipyrone, disopyramide, domperidone, dopamine, doxycycline, enalapril, ephedrine, epinephrine, ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradiolms etoposide, Eucalyptus globulus, famotidine, felodipine, fenofibrate, fenoterol, fentanyl, flavin-mononucleotide, fluconazole, flunarizine, fluorouracil, fluoxetine, flurbiprofen, furosemide, gallopamil, gemfibrozil, gentamicin, Gingko biloba, glibenclamide, glipizide, clozapine, Glycyrrhiza glabra, griseofulvin, guaifenesin, haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone, ipratropium hydroxide, ibuprofen, imipenem, indomethacin, iohexol, iopamidol, isosorbide-dinitrate, isosorbide mononitrate, isotretinoin, ketotifen, ketoconazole, ketoprofen, ketorolac, labetalol, lactulose, lecithin, levocarnitine, levodopa, levoglutamid, levonorgestrel, levothyroxine, lidocaine, lipase, imipramine, lisinopril, loperamide, lorazepam, lovastatin, medroxy-progesterone, menthol, methotrexate, methyldopa, methyl-prednisolone, metoclopramide, metoprolol, miconazole, midazolam, minocycline, minoxidil, misoprostol, morphine, multivitamin mixtures and combinations and mineral salts, N-methylephedrine, naftidrofuryl, naproxen, neomycin, nicardipine, nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine, nimodipine, nitrazepam, nitrendipine, nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline, nystatin, ofloxacin, omeprazile, ondansetron, pancreatin, panthenol, pantothenic acid, paracetamol, penicillin G, penicillin V, phenobarbital, pentoxifylline, phenoxymethylpenicillin, phenylephrine, phenylpropanolamine, phenytoin, piroxicam, polymyxin B, povidone iodine, pravastatin, prazepam, prazosin, prednisolone, prednisone, bromocriptine, propafenone, propranolol, proxyphylline, pseudoephedrine, pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol, riboflavin, rifampicin, rutoside, saccharin, salbutamol, salcatonin, salicylic acid, simvastatin, somatotropin, sotalol, spironolactone, sucralfate, sulbactam, sulfamethoxazole, sulfasalazine, sulpiride, tamoxifen, tegafur, teprenone, terazosin, terbutaline, terfenadine, tetracycline, theophylline, thiamine, ticlopidine, timolol, tranexamic acid, tretinoin, triamcinolone acetonide, triamterene, trimethoprim, troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin E, folinic acid, zidovudine.
Preferred active ingredients are those which can be dissolved in particularly high concentration in the solvents according to the invention. These include acetylcysteine, acetylsalicylic acid, anipamilxc3x97HCl, phenylbutazone, captopril, esuprone, flecainide, nexopamil, nitrofurantoin, (+)-pseudoephedrinexc3x97HCl, selegilinexc3x97HCl, hydantoins such as 5,5-diphenylhydantoin, benzodiazepines such as diazepam, chlordiazepoxide, pyrazolone derivatives such as diphenylbutazone, aminophenazone, dimethyl-aminophenazone, carbamates such as meprobamate, barbiturates such as phenobarbital, pentobarbital, aminobarbital, antibiotics such as amoxicillin, ciprofloxacin, chloramphenicol, oxytetracyclines, virustatics such as acyclovir, famcyclovir, and antimycotics such as ketoconazole, fluconazole and itraconazole, sulfonamides such as sulfamethoxazole, sulfamoxole, sulfathiazine, steroids such as prednisolone, cyproterone acetate, hydroxyprogesteronecaproate, sulfonamide potentiators such as trimethoprim, non-steroidal antirheumatics (NSAR) such as ibuprofen, diclofenac, mefenamic acid or theophylline. The fat-soluble vitamins A, E, K and their derivatives, such as vitamin A palmitate, acetate or propionate, vitamin E acetate or nicotinate, can be mixed in any ratio with the compounds according to the invention; the same applies to vitamin C. The lower viscosity is also advantageous, which often has a disadvantageous effect on use of oils or semisynthetic fatty acid esters. Also suitable are the xcex2-blocker class, Ca antagonists, ACE inhibitors, xcex1-blockers, H2 antagonists, lipid lowering agents, antihistamines, antiepilectics and NS psychopharmaceuticals.
Particular suitable are benzocaine, chloramphenicol, cyclosporin, clotrimazole, 5,5-diphenylhydantoin, fenofibrate, furosemide, is gallopamilxc3x97HCl, glibenclamide, hydrochlorothiazide, ketoprofen, ibuprofen, indometacin, naftidrofuryl, nifedipine, nitrendipine,. omeprazole, paracetamol, pentoxifylline, prazosin, propafenonexc3x97HCl, sulfamethazine, sulfamethoxazole, sulfathiazole, sulindac, tolbutamide, tramadol and zotepine.
The choice of suitable vehicles and ancillary substances depends on the nature of the active ingredient and, in particular, of the formulations.
Examples of conventional vehicles or ancillary substances which are suitable for the purposes of the present invention are
solvents which are miscible with the solvents according to the invention, such as water, ethanol, glycerol, 1,2-propylene glycol, low molecular weight polyethylene glycols, tetraglycol, dimethylacetamide, dimethylformamide, benzyl alcohol, neutral oils such as paraffin, olive oil, sesame oil, arachis oil, castor oil or mixtures of triclycerides of saturated vegetable fatty acids;
salts to adjust the tonicity in order preferably to obtain isotonic solutions;
buffers to adjust the pH in order to obtain, in particular, formulations with the physiological pH;
agents to increase the viscosity, eg. on topical use, such as polyethylene glycols, polyvinylpyrrolidone or polyacrylates and cellulose ethers;
stabilizers such as antioxidants to protect medicinal substances which are sensitive to oxidation, for example sulfite, sodium sulfoxylate, cysteine, ascorbic acid, xcex1-tocopherol or else compounds which complex heavy metal ions, such as EDTA disodium salts;
preservatives such as antimicrobial agents in bacteriostatic or fungistatic concentrations, for example phenylmercuric nitrate, thiomersal, benzethonium chloride, benzalkonium chloride, phenol, cresol or chlorobutanol;
masking flavors which are used, in particular, for oral preparations;
and other vehicles and ancillary substances which can conventionally be used for formulating the drugs according to the invention.
The cosmetic compositions are in the form of, in particular, creams, gels, ointments or solutions. The cosmetic compositions are formulated in a conventional way, for example as indicated above for topical pharmaceutical compositions.
The following examples describe the invention without restricting it: